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org/JAFC Review

Natural Food Colorants and Preservatives: A Review, a Demand, and

a Challenge
Cláudia Novais, Adriana K. Molina, Rui M. V. Abreu, Celestino Santo-Buelga, Isabel C. F. R. Ferreira,
Carla Pereira,* and Lillian Barros*

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ABSTRACT: The looming urgency of feeding the growing world population along with the increasing consumers’ awareness and
expectations have driven the evolution of food production systems and the processes and products applied in the food industry.
Although substantial progress has been made on food additives, the controversy in which some of them are still shrouded has
Downloaded via 179.0.29.84 on March 22, 2023 at 21:14:11 (UTC).

encouraged research on safer and healthier next generations. These additives can come from natural sources and confer numerous
benefits for health, beyond serving the purpose of coloring or preserving, among others. As limiting factors, these additives are often
related to stability, sustainability, and cost-effectiveness issues, which justify the need for innovative solutions. In this context, and
with the advances witnessed in computers and computational methodologies for in silico experimental aid, the development of new
safer and more efficient natural additives with dual functionality (colorant and preservative), for instance by the copigmentation
phenomena, may be achieved more efficiently, circumventing the current difficulties.
KEYWORDS: natural food additives, colorants, preservatives, copigmentation, molecular dynamics

1. INTRODUCTION a promising solution. However, to obtain benefits such as

Improving food quality and safety is of paramount importance antioxidant or antimicrobial activity, the concentration of the
for human well-being. Since prehistoric times, man has been compounds commonly used as dyes are usually high, not
improving the diet and the way of hunting, domesticating meeting the requirement of the admissible daily intake (ADI).5
Research and development of new molecules through new
animals and vegetables, preserving food by physical methods,
chemical approaches, with the modification of natural
and finally by adding molecules to food to enhance flavors or
molecules already known, so that they can develop a better
to preserve it.1
and double performance (colorant plus preservative), may be a
Over the years, several ingredients have performed useful
path to be followed by the scientific community to circumvent
functions in a diversity of foods, providing an affordable,
the difficulties and monetize the use of these additive
nutritious, tasty, colorful, and safe food supply, with food
molecules in the food industry.
additives and technology developments playing crucial roles.2
1.1. Food Additives, Food Industries, and Their
Their use in the food industry is fundamental, allowing loss
Demands. The use of pesticides, irradiation, food additives,
reduction, quality increase, shelf life extension, new for-
and even trace substances in the production and preservation
mulations development, and standardization, thus meeting the
of food, has generated a high concern among consumers, due
increasingly challenging market demands.3 Used in all types of
to the possible short, medium, and long-term health effects.6
foods, additives are becoming increasingly prevalent and
These issues and health concerns are even more obvious in
important in human nutrition, being subjected to strict
highly processed and modified food products, which have been
regulation, despite the controversy caused by conflicting
rising in the last decades and hold a higher additive load.
results obtained in a large number of studies involving these
Currently, there is a general pressure for innovation in the food
compounds, along with different governments interpretations.4 and biotechnology industries in order to provide food products
Today, globally, hundreds of additives are added to food, while adapted to the modern lifestyle (highly attractive and perfect
many others have been banned over the years.1 foods, with particular organoleptic characteristics as well as a
With an increasingly competitive market, it is essential to long shelf life) but, at the same time, healthy and safe food.7−9
reduce production costs and monetize existing products, while
ensuring food safety and quality. Since coloring and preserving
additives are among the most important ones in the food Received: November 25, 2021
industry, improving the appearance and preservation of Revised: February 10, 2022
foodstuffs, several studies have been focusing on finding new Accepted: February 16, 2022
solutions and/or improving existing alternatives. Finding Published: February 24, 2022
compounds that can have both capacities (colorant and
preservative) and, additionally, exert bioactive functions can be

© 2022 American Chemical Society https://doi.org/10.1021/acs.jafc.1c07533

2789 J. Agric. Food Chem. 2022, 70, 2789−2805
Journal of Agricultural and Food Chemistry
To meet most of these conditions, various processes and
ingredients such as food additives (colors, sweeteners,
preservatives, emulsifiers, acidifiers, etc.) have been used,
which have been developed both to prevent food spoilage and
to improve its taste and appearance. However, studies of their
long-term effects are still needed.10
As a principle, food additives should only be employed if
their technological effect is justifiable and cannot be met by
other feasible methods. Moreover, these compounds must not
pose a health risk to consumers at the level of use proposed.11
The most important regulatory bodies that set the conditions,
legislate, and oversee the approval and standardization of food
additives in the world are EFSA, the European Food Safety
Authority, in the European Union (EU), and the FDA, Food
and Drug Administration, in the United States (U.S.). Also,
JECFA, the Joint Expert Committee on Food Additives of the
Food and Agriculture Organization (FAO)/World Health
Organization (WHO), and the Codex Alimentarius are also
key bodies responsible for carrying out studies and safety risk
assessments and issuing declarations. Codex Alimentarius is
the point of reference for other official food authorities around
the world for meeting national and international quality
standards in the export of processed foods.11 In the EU, the
classification of food additives depends on the function in food,
which is divided into 26 functional classes.10 On the other
hand, in the United States, additives are reduced into 2 or
more classes, where 3000 are allowed by the FDA, which are
classified into preservatives, nutritional additives, colorants,
flavorings, texturizers, and miscellaneous agents.12
In Europe, all food additives are given a specific code that
begins with the letter E followed by three or four digits,
referred to as the E-number, making it easier for the consumer
to understand the label of foodstuffs from different European
countries. The added amount of additive is scrupulously
calculated for the type of food, so as not to exceed the
acceptable daily intake (ADI), which is the cumulative amount
of a specific additive that, consumed daily, has no harmful
effect on health. The same code number is also used by the
Codex Alimentarius.13
However, despite their manifest benefits, it is worth noting
that a large proportion of approved food additives are synthetic
in nature, and when used incorrectly, a range of side effects,
toxicity, and other adverse reactions have carcinogenic
capacities.9 In this regard, regulatory agencies worldwide
have carried out extremely stringent evaluation procedures,
from which several synthetic additives have been banished due
to gastrointestinal, respiratory, dermatological, and neuro-
logical adverse reactions.14−17
However, a global consensus on food additive legislation has
not yet been established. Some substances can be added to
foods in the U.S. and banned in the EU, such as the
antimicrobials sodium sorbate (E201) and calcium sorbate
(E203) and the colors FD&C green no. 3 (Fast Green (E143))
and citric red no. 2 (E121). On the other hand, the
antimicrobial sodium methyl p-hydroxybenzoate (E219) and
the coloring agents carmoisine (E122), amaranth (E123), and
patent blue (E131) are allowed in the EU and banned in the
U.S.11,12 With all this, there are contradictions in the
legislation, which leads to problems in food safety and
obstacles to international trade. Likewise, there is no
established definition for preservatives, antioxidants, colorants,
or natural sweeteners; only natural flavorings have the same
legislation in both the EU and the U.S., which has led to
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erroneous use at a general level for all classes of additives, thus
giving erroneous interpretations of what is natural and what is
synthetic. For all these reasons, the need for a uniform
legislation on natural additives is evident, due to their wide
interest, especially in developed countries.18
At the same time, there is a growing demand for food
products with health promotion and disease prevention
capacity.6,19,20 They are known as functional foods, with a
currently accepted worldwide conceptual definition as foods
that “have been satisfactorily shown to affect one or more
target functions in the body, in addition to appropriate
nutritional effects, in a way that is relevant to an improved state
of health and well-being and/or reduced risk of disease”.21 In
this sense, natural additives may also be included in this
concept as they possess a high biological quality and are able to
present health-promoting abilities.
2. FOOD COLORANTS
Organoleptic characteristics largely determine the acceptance,
selection, and subsequent consumption of foods. Color can be
considered one of the most impressive and charming attributes
of foods, and although natural food products have their own
color, the different processes they undergo and factors, such as
the presence or absence of oxygen, metals, light, pH, and water
activity, can produce undesirable modifications. To circumvent
this problem, chemical compounds that impact color are
intensely used by food industries, while an increasingly strict
and regulatory legislation accompanies these advances to
ensure good manufacturing practices and total consumer
safety.22−9
A color additive, or food colorant, is according to the FDA,
“any colorant, pigment or substance that, when added or
applied to a food, drug or cosmetic, or to the human body, is
capable (alone or through reactions with other substances) of
imparting color”.24
Differences in chemical structures, sources, and purpose of
use can make classifications of colorants complex, and they can
be classified according to several criteria: origin (natural,
natural-identical, or synthetic; organic and inorganic),
solubility (soluble and insoluble), and hiding power (trans-
parent and opaque). The most used form is according to their
origin, either natural or artificial. Natural dyes can be obtained
from plant tissue (e.g., curcumin, carotenoids, anthocyanins,
betalains, or chlorophylls), animal cells (carminic acid and
kermesic acid), metabolism of microorganisms (carotenoids
and chlorophylls), or mineral sources (titanium dioxide or
calcium carbonate). Artificial colorants are achieved by
chemical synthesis, and they are not found in nature.25
All these dyes do not impart an aftertaste when added at a
certain concentration, and their use in the food industry is
mainly in confectionery, bakery, beverages, dairy products, and
meat.26
2.1. Synthetic Colorants. Preferred by the industry,
synthetic colorants are chemically or physically modified
products with desirable characteristics for manufacturing,
such as high purity, coloring capacity, stability, brightness,
wide range of shades, uniformity and reproducibility in
production, and low cost compared to natural colorants.13,9
As science has advanced, more artificial colors have been
developed that are very stable and allow a wide range of colors,
which has led to their increasing use in the food industry.
However, despite the continuous research for synthetic
compounds, many of them are for humans, and based on the
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Figure 1. Natural colorants approved by the European Union, their shade, and functionality.
latest discoveries regarding the side effects and toxicity
problems of some synthetic dyes, natural alternatives have
become more appealing for consumers worldwide.5 Further-
more, in order to detect the presence of synthetic food colors
in food, highly specific methods and procedures have been
developed, which also make it possible to determine the
probability of side effects and toxicity in the medium- and
long-terms.27
Studies have reported that the intake of artificial colorings,
mainly nitro derivatives, of the azo type (E102, E110, E122,
E123, E124, and E129) can cause some health problems. The
European Parliament, in 2008, decreed those foods containing
one or more of these color additives must be labeled with the
name or the E-number information followed by the warning
“may have an adverse effect on activity and attention in
children”.12 Tartrazine (E102), a lemon yellow, used in
candies, ice cream, cereals, soups, jellies, cakes, soft drinks,
and other foods, is one of the most controversial color
additives regarding its safety. Obsessive-compulsive disorders
and hyperactivity in children have been linked to its intake, as
well as its mutagenic capacity, due to its interaction with
human serum proteins.16,17,28 In recent studies, administration
of tartrazine at ADI levels in mice showed increased lipid
oxidation and changes in biochemical markers in brain tissue
hematotoxin,29 immunotoxin effects, renal disorder, and
increased DNA abnormalities.28,30 Sunset yellow (E110),
obtained from petroleum-derived aromatic compounds, has
been related to increased pro-inflammatory activity, as have
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carmoisine (E122), allura red (E129), and ponceau 4R
(E124), which also bind to human and bovine serum
albumin.17 Amaranth (E123), a dye that imparts red color to
foods such as in candies, ice cream, and beverages, allowed in
the EU but banned in the U.S. due to carcinogenicity, has
shown a high genotoxic effect on cultured human lympho-
cyte.31 It is important to note that there are colors that are
permitted in the European Union, but the same is no longer
the case in the United States.32 Given these contradictions and
the impact of artificial colorings in health, more and more
emphasis is being placed on research on sources of natural
origin, both for their safety and health-promoting proper-
ties.33−35
Despite the controversy surrounding food colors, there is
high pressure on the search for natural colors because of the
role they play in the food industry. In the U.S. and the EU,
some alternatives have been developed with excellent results,
among which molecules such as carotenoids, anthocyanins,
annatto, and paprika stand out with possible characteristics
that could substitute their synthetic counterparts. However,
these compounds have disadvantages such as instability with
respect to pH and temperature, loss of color due to oxidation,
higher manufacturing cost, and greater quantity of the product
with respect to synthetic colorants.36
2.2. Natural Colorants. Until the middle of the last
century, the dyes used in food were of natural origin, for
example, saffron (obtained from stigma and styles of the flower
of Crocus sativa L.), orcein (extracted from certain lichens),
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Journal of Agricultural and Food Chemistry
cochineal (obtained from certain insects of the family Coccidae,
a parasite of some cacti), caramel (sugar paste turned into
syrup), red beet (aqueous extract of the red beet root), alizarin
(obtained from tropical woods), and indigo (from the indigo
plant or glasto, a European shrub).13,26 Today methods of
collection, extraction, purification, stabilization, and stand-
ardization for various natural food colors are available, such as
anthocyanins, betalains, chlorophylls, carotenoids, etc. These
include different groups of chemical compounds that can be
used directly as dyes or in chemically modified forms to
produce different hues, ranging from green to yellow, orange,
red, blue, and violet, depending on the compounds or their
stabilized forms.9,37
Curcumin (E100), a purified turmeric pigment extracted
from the dried rhizomes of Curcuma longa L., is a widely used
food coloring that imparts orange color and is used in mustard,
yogurt, bakery products, dairy products, ice cream, and salad
dressings.38 Carminic acid (E120) is the main pigment present
in the insect Dactylopius coccus Costa (cochineal), which when
complexed with aluminum, turns into bright red. This dye is
quite expensive compared to other natural reds, such as
anthocyanins, although it is considered technologically
important due to its stability. It replaces the use of potentially
toxic synthetic dyes; however, the food product cannot be
classified as vegan/vegetarian or kosher because it contains an
animal product.39 It is used in jams, jellies, bakery products,
dairy products, and noncarbonated beverages.38 Chlorophylls
and chlorophyllins (E140) occur naturally in plants; of the
different existing chlorophylls, only two are used in the food
industry as colorants, mainly due to their difficult stabilization;
more stable copper complexes of them are also authorized
(E141). The commercial chlorophyll dyes used are extracted
from alfalfa and have been employed in dairy products, soups,
beverages, and sugar confectionery.38 Annatto (E160b),
extracted from the seeds of the fruits of Bixa orellana L. tree,
has the carotenoids bixin and norbixin as its main constituents,
which are yellow to orange and provides a slightly redder color
than β-carotene. It is used in cakes, cookies, rice, dairy
products, flour, fish, soft drinks, snacks, and meat prod-
ucts.39−41 Paprika extract, capsanthin, and capsorubin (E160c)
also consist of carotenoids, with an orange to red color. Many
other carotenoids used in food, namely, β-carotene, lutein,
violaxanthin, neoxanthin, β-cryptoxanthin, fucoxanthin, lyco-
pene, and astaxanthin, are mainly applied to sauces, marinades,
seasoning mixtures, toppings, beverages, milk, and others.18
The main anthocyanins (E163) in nature are glycosides of the
aglycones cyanidin, delphinidin, malvidin, pelargonidin,
peonidin, petunidin, with colors ranging from red, purple,
violet, and blue, with over 700 anthocyanins having been
identified.42−44 Their main uses are in soft drinks, confection-
ery, and fruit preparations.18 Betalains are pigments with
similar colors to anthocyanins, ranging from red-violet
(betacyanins) to yellow-orange (betaxanthins). However,
betanin (E162) derived from beets is the only betalain with
legislated use and has been the most massively utilized natural
pigment in industry to replace Allura red AC (E129; FD&C
Red 40).39 Its use is approved to provide a red hue to candies,
ice cream, meat substitutes, and beverages.32,45 Despite the
limitations of using betalains as a food dye due to their
sensitivity to light and heat, they have several advantages over
other natural dyes, such as higher water solubility and strong
dyeability and stability in neutral and acidic pHs, and given
their range of colors, there is a great potential to create a
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gradient of natural color shades from these pigments.9,39,46,47
All natural dyes approved by the European Union are collected
in Figure 1.
An alternative to natural blue dyes would be the
phycocyanin pigments from Spirulina (A. platensis). The
search for a vibrant and stable source of natural blue dyes
has been stealthy, and since anthocyanins, which may have a
blue color between pH 5−7, tend to change their hue
depending on the pH value and water content, these would be
a good alternative.48 Spirulina, a Gram-negative cyanobacte-
rium, produces picocyanobacteria that can be isolated, and
phycocyanin can be recovered as a phycocyanin protein
complex. Currently, picocyanobacteria from Spirulina provide
the only natural blue dye approved in the United States and
Asia, although it is not yet allowed in the European Union.49,50
Initially, phycocyanins were used only to color sweets and
chewing gums, but innovations in food processing have
allowed the range of phycocyanin-colored products to be
extended to dairy products, soft drinks, and cosmetics.51 They
have been mainly applied in beverage products, but low pH
stability issues continue to limit a wider application.
Another approach to produce natural dyes would be
microorganisms such as bacteria and fungi. These can generate
a range of natural pigments that botanical sources are unable to
provide, they are less constrained by seasonal variation issues,
and their extraction can be simplified and easily scaled to
industries.52,53 Bacteria, typically easier to modify genetically,
with a shorter life cycle, are an opportunity to expand research
in pigment production, which is still poorly understood.54 A
laboratory at Rensselaer Polytechnic Institute in Troy, New
York, has developed a way to use E. coli and glucose to produce
anthocyanins at industrially relevant levels of g/L.55 Regarding
fungi, nontoxic Monascus sp., which produces six large
polyethylene pigments ranging from yellow to red, has so far
not gained U.S. or EU approval due to concerns over citrinin
production (a potent fungal toxin), although it has been used
successfully in Asia for hundreds of years.52,54 However, there
are concerns with customer acceptance of food coloring
coming from microbes.
Despite the instability associated with these types of dyes,
some natural food colors have proven to be as effective as
those derived from chemical synthesis, with the subsequent
benefits of being safer and providing health benefits, in
addition to conferring organoleptic characteristics, thus
exerting two or more benefits as food ingredients. In fact,
several food additives exerting coloring effects also act as
antioxidants and even preservatives, also conferring functional
properties to food products.56,57 The consumption of func-
tional foods has been increasing, due to the healthy properties
that they provide to the consumer when they are adequately
included in the daily diet.21,57,58
Many companies have been substituting artificial colorants
for natural ones in order to satisfy consumers’ demand, due to
the fact that they not only have the capacity of pigmentation
but also have health properties.26,36,57
It should be emphasized that, in general, the stability can be
understood as one of the most important factors for the use of
natural food colorants, since unpleasant organoleptic character-
istics appear when unstable food colors are applied, leading to
food rejection by consumers.5 Thus, several approaches have
been developed to solve this problem,7,45,59 while other studies
have focused on finding different sources of promising food
colorants, so that a growing and emerging number of studies
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are seeking to explore new sources of natural colorants, actually
there are already several available reports exploring the
potential of novel alternatives from plants, insects, fungi,
bacteria, and algae.60−64 For that purpose, extraction and
stabilization techniques have also been assessed to allow their
application in the food industry, in order to compete with
artificial solutions in terms of coloring efficiency and color
stability over the products storage time.
3. FOOD PRESERVATIVES
Food products are susceptible to deterioration by micro-
biological, enzymatic, physical, or chemical processes, which
can reduce their quality, nutritional value, and safety as well as
lead to undesirable changes in their physicochemical and
sensorial attributes. With this in mind, a variety of biological,
physical, and chemical methods for food preservation have
been developed to extend the shelf life of foods and keep them
safe for consumers, without modifying their sensory character-
istics.65 The application of preservatives in food processing is
one of the current food preservation techniques which, besides
maintaining the quality of food, helps control contaminations
that can lead to foodborne diseases. They can be natural or
synthetic substances and be subdivided into three groups:
antimicrobials, antioxidants, and antibrowning agents.66
Antimicrobials have been applied to control and prevent
natural spoilage by microorganisms; antioxidants are used as
preservatives to limit or delay biological and chemical spoilage
of foods by preventing auto-oxidation of pigments, flavors,
lipids, and vitamins; and last, antibrowning agents are used to
prevent browning of foods, which can occur at any time during
handling, processing, and storage.67
3.1. Antimicrobials. Antimicrobial compounds can be
naturally present in foods or added to delay and/or prevent the
proliferation and growth of natural microorganisms responsible
for the spoilage of foods (bacteria, yeasts, and molds) as well as
to prevent/control contamination by pathogenic microorgan-
isms, thus ensuring food safety and quality.68
The use of antimicrobial additives increases the shelf life of
food, but in high concentrations, these compounds can
promote an unpleasant taste, strong odor, altered viscosity,
and color retention, with their choice dependent on the
antimicrobial properties and spectrum of activity, the
physicochemical composition and properties of the food
matrix, and the nature of the storage and preservation
methods.36,69 They can be either natural or synthetic.
3.1.1. Synthetic Antimicrobials. Several artificial preserva-
tives have been officially recognized by the regulatory
community to be used as food antimicrobials.70 These are
substances of chemical origin that prevent or inhibit the
proliferation and growth of bacteria, yeasts, and molds. Among
those approved for food applications, inorganic acids and their
sodium salts, such as nitrite and sulfate, and weak organic
acids, such as benzoic acid, sodium benzoate, sodium
propionate, and others, are included.71 Despite the beneficial
effects and important role of these compounds in the
preservation of food products, the use of chemical antimicro-
bials in food is still a subject of discussion and acknowledged
controversy, as the results of reported research do not
demonstrate consistency. Indeed, it is not simple to provide
clear conclusions on efficacy and safety, and synthetic
antimicrobial food additives, such as sorbates, nitrates, and
sulfites, have demonstrated various side impacts on human
health.72 Although the reports are disturbing, these are
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indispensable in the food industry, and the only way to reduce
their application would be to find a nontoxic substitute with
the same preserving effect. The use of these compounds
decreases the incidence of food spoilage and food poisoning.73
Long-term exposure to sodium benzoate (E211) is claimed to
be nonhazardous, but this has yet to be proven, and while
some researchers consider sodium sulfate (E221) to be
hazardous to health, others say otherwise. Sodium sorbate
continues to raise questions and concerns; some studies have
shown that it may be genotoxic to human lymphocytes in vitro,
depending on the dose used.74,75 Over the years, extensive
studies have been conducted on sorbates (E200−E203) and
their health implications, in which they have been described as
possible genotoxic and mutagenic, but other studies report that
this is not relevant.76−78 Also, parabens (E214−E218), generic
name of the group of antimicrobials that are alkyl esters of p-
hydroxybenzoic acid, have been widely used due to the
absence of odor and/or taste; however, it has been shown that
the use of parabens can induce migratory and invasive activity
in human breast cancer cells in vitro.79,80 Nitrites (E249 and
E250) and nitrates (E251 and E252) are other antimicrobials
used in food. The second group has recently been restricted in
the EU and can only be added to meat for slow curing. Nitrites
are used in meat for color formation, flavor enhancement, and
antimicrobial activity and are the only food additives able to
inhibit botulinum toxin, justifying their use in the food industry
by their benefit/risk, despite having shown carcinogenic effects,
among other harmful effects to humans.81 In the European
Union, their use is only permitted in the lowest possible
dosage. Nitrates and nitrites can also be found naturally in
untreated fruits and vegetables and may also be involved in the
formation of nitrosamines.82−88 Sulfites (E220−228) are used
in foods such as wine, dried fruit, dehydrated cookies, and fish,
among others and can act as such or combined with organic
acids. However, they are known to cause adverse reactions in
sensitive people and have shown cytotoxic and carcinogenic
effects for rats and humans; also they are known to induce
deterioration of thiamine (vitamin B1) in foods. 89−91
Propionic acid (E280) and its sodium (E281), calcium
(E282), and potassium salts (E283) are used primarily in
bakery products to prevent mold and other fungal contami-
nation. There are not many studies on their toxicity, although
they have been reported to induce onion root tip
abnormalities, producing chromotoxic effects and, conse-
quently, chromosomal anomalies and have also been linked
to irritability, restlessness, inattention, and sleep disturbances
in some children.12,72
Other effective antimicrobial agents are acetic, benzoic, and
lactic acids. Malic (E296), fumaric (E297), citric (E330), and
other organic acids are also used, having, however, limited
antimicrobial activity; in fact, they are more often used as
flavoring agents. Generally, the mechanisms of action of weak
organic acids are based on the inhibition of nutrients.72 Acetic
acid (E260), the main component of vinegar, is commonly
used in condiments including mustard, salad dressings, and
mayonnaise to inhibit the growth of fungi and bacteria. It is
more active against bacteria and yeasts than in molds. Benzoic
acid and sodium benzoate (E210 and E211) tend to be used in
foods where the pH is low, such as fruits, mayonnaises, pickled
vegetables, and beverages, exerting their antimicrobial activity
against yeasts and fungi, including inhibition of aflatoxin
production. Lactic acid (E270) is incorporated into acidified
food products to provide additional stability and safety. It is
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Figure 2. Natural compounds with preservative capacity, in use or under research. *Additive allowed as a colorant but not as an antioxidant.
**Additive still under study, not yet permitted in the EU.
effective in reducing microbial communities on meat surfaces
and is even more efficient than acetic acid in reducing E. coli
O157:H7.72
3.1.2. Natural Antimicrobials. Due to the potential of
synthetic preservatives to cause health problems, consumers
and companies are trying to replace synthetic preservatives
with natural preservatives (Figure 2), which can be achieved
from sources such as plants, bacteria, fungi, animals, and algae
and are considered safer for humans and the environment.66
3.1.2.1. Plant-Based Antimicrobials. Depending on the
type, nature, and concentration, various plant extracts (e.g.,
herbs and spices) have preservative aptitudes, with antimicro-
bial activity against various microorganisms and can thus
increase the storage life of foods.66 Thanks to compounds,
such as phenols, alcohols, aldehydes, ketones, among others,
these can be alternative sources of new antimicrobial
compounds, having already been reported by several
researchers.92−95 Antimicrobial compounds present in plants
include essential oils, phenolic compounds, polypeptides,
lectins, and alkaloids. Additional categories of substances,
such as polyamines, organic acids, glycosides, and glucosino-
lates, have also shown potential as natural antimicrobials.72
Essential oils (EO) are produced mainly by aromatic plants
and are bioactive, complex liquid volatile compounds
characterized by an intense flavor and smell. In the food
industry, they are mainly used as flavoring agents; however,
they may also act as natural antioxidants and antimicrobials in
food preservation. The principal plants used for EO extraction
include lemongrass, peppermint, lavender, geranium, thyme,
oregano, sage, rosemary, basil, vanilla, clove, fennel, cumin,
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cinnamon, and anise. The main compounds present in EO that
confer antimicrobial activity are terpenes, aldehydes, ketones,
aliphatic alcohols, organic acids, phenolic compounds,
saponins, glucosinolates, and thiosulfinates.98 Rich in terpenes,
such as linalool, eugenol (from clove and cinnamon), thymol
(from thyme and oregano), carvone, carvacrol (from oregano),
citral, limonene and their precursors, and many other
substances, EO possesses antimicrobial properties against a
broad spectrum of food-borne microorganisms, including
spoilage and pathogenic bacteria and fungi.92,99 Carvacrol,
for example, found in high concentrations in oregano, has
antimicrobial and antifungal power, even at low concen-
trations, and these effects can be enhanced if cinnamaldehyde
and nisin are also present. Thymol, an isomer of carvacrol,
shows the same antibacterial and fungicidal activity, including
inhibitory effects against Aspergillus species in vitro.100 Ozogul
et al.101 revealed that an EO-based nanoemulsion (thyme and
rosemary) can be used as a preservative ingredient due to its
capacity to improve microbiological and organoleptic proper-
ties in rainbow trout fillets. Generally, EO produces a better
inhibitory effect against Gram-positive than Gram-negative
bacteria, since they are lipophilic compounds and can
penetrate Gram-positive bacteria.102 Their capabilities can be
further enhanced by synergism with bacteriocins or even food
constituents, depending on the purpose. While essential oils
are generally incorporated into foods by direct mixing,
immersion, and spraying methods, they recently found
application in bioactive packaging, encapsulation, and nano-
technology. Other considered applications are edible films and
coatings with incorporated bioactive substances, which have
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been targeted especially in food preservation, acting as carriers
for EO and thus controlling microbial growth.66 In this
context, the EO of Origanum majorana encapsulated in
terpinen-4-ol enriched chitosan nanoemulsion has been
shown to be a considerable preservative of stored food
products against contamination by fungi, aflatoxin B1 (AFB1),
and lipid peroxidation.103 Consequently, these bioactive
encapsulated compounds could be approved as a suitable
antifungal agent to extend the shelf life of food products.
Furthermore, the use of EO of clove, oregano, sage, ginger, and
thyme, alone or in combination, has demonstrated the ability
to limit the oxidative process in food matrixes, such as meats
and dairy products, due to their richness in phenolic
compounds. In this regard, various EO have shown remarkable
antioxidant activity, being considered effective in retarding
lipid oxidation in fish and meat products and applied as
preservatives in fish supplements.104 The only drawback of
EOs is that, even at low concentrations, they can be toxic to
humans, so more extensive studies should be conducted to
determine their actual effects on the human body and to
establish an ADI.105 On the other hand, weak organic acids
(citric, acetic, malic, lactic, tartaric, etc.), present in oranges,
lemons, apples, and grapes, along with other fruits and juices,
are natural flavoring and acidifying agents in acidified foods
and can prevent various contaminating microbes.72
3.1.2.2. Animal and Microbial-Based Antimicrobials.
Other bioactive compounds that can be applied in food
preservation are those derived from animal secretions or
defense systems. Antimicrobial peptides (AMPs), for example,
are oligopeptides with a broad spectrum of activity against
bacteria, fungi, protozoa, and some viruses. They are isolated
from natural sources such as plants, insects, amphibians,
crustaceans, and marine organisms, and those already used as
food additives have been claimed to possess positive health
effects with unreported toxicity.66 Lysozyme, lactoferrin,
ovotransferrin, pleurocidin, defensins, chitosan, etc. are other
possible antimicrobials of animal origin. Lysozyme, from
various sources, has antimicrobial activity, particularly against
Gram-positive bacteria. This enzyme is broadly used as
preservative in meat, fish, milk, and dairy products as well as
fruits and vegetables, although it has a limited action against
bacteria and fungi. Its activity can be increased when used in
synergy with other preservatives, as nisin.12 Lactoferrin has
iron-binding capacity and is found in milk and other secretions.
Two AMPs isolated from fish are pleurocidin and protamine,
which have activity against the bacterium Listeria mono-
cytogenes as well as other food-borne microorganisms.
Cathledicin, found in mammals, shows activity against bacteria,
fungi, and viruses.106 Salmin, a cationic AMP derived from
salmon milt, was found to slow the growth of Listeria
monocytogenes in smoked salmon.107 The use of chitosan and
its derivatives (extracted from the exoskeletons of crustaceans
and arthropods) in the food and pharmaceutical industries is
mainly due to their preservative effects. They can find
application in the development of edible films and coatings
used in the food industry and are also employed in
combination with other molecules such as xylan and
glucose.108 In fact, chitosan fibers combined with flavonoids
have shown excellent antioxidant activity.109 The application of
chitosan in meat and seafood conferred significant oxidative
stability by reducing the thiobarbituric acid value and retarding
lipid oxidation during storage.65 One enzyme that has attracted
attention for its bactericidal or bacteriostatic properties is
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lactoperoxidase (LPO), due to its use as a natural antimicrobial
agent in food packaging. The application of chitosan with LPO
to coat trout fillets preserved their quality.110 Likewise,
incorporating LPO in alginate coatings had an inhibitory
effect on Listeria monocytogenes and E. coli bacteria in rainbow
trout fillets.111
Beyond the demonstrated activity of AMPs against various
food-borne pathogens,112 many research studies have also
reported that protein hydrolysates and peptides obtained from
goat milk, blue mussel, Pacific hake fillet, tuna backbone, or
beef can exert a higher antioxidant activity than α-tocopherol,
BHT and BHA (butylated hydroxytoluene and butylated
hydroxyanisole, respectively) additives, being therefore val-
uable alternative preservative and functional ingredients to be
used in food to decrease oxidative change during storage.109,113
Food biopreservation using microbes and microbial
metabolites to increase food safety and extend shelf life is
one of the alternatives to chemical treatments. Lactic acid
bacteria (LAB) are the main candidates, and several species
have been used as cultures to produce fermented products
such as sausages, cheeses, or yogurts. Antibacterial compounds
such as bacteriocins, organic acids, reuterin, diacetyl, ethanol,
CO2, H2O2, and lactic acid derivatives are generated by LAB.72
Bacteriocins are ribosomally synthesized antimicrobial
peptides that are produced by bacteria and have been
employed in the preservation of meat and vegetable products
for having bactericidal or bacteriostatic effects.98,114 Bacter-
iocins used in food are synthesized by strains of Carnobacte-
rium, Lactococcus, Lactobacillus, Pediococcus, Leuconostoc, and
Propionibacterium and the major bacteriocins include nisin,
pediocin, diplococcin, plantaricin, acetylphilin, helveticin,
bulgarican, and lactacin.72 They can also be used in bioactive
packaging applications to control food pathogens by
preventing the growth of microorganisms on the food surface
through contact of the packaging material.115 Nisin is an
antimicrobial peptide naturally synthesized by Lactococcus lactis
and is the only bacteriocin recommended for global application
as an additive in the food industry with GRAS (generally
recognized as safe) status and excellent antibacterial proper-
ties.116 It has activity against Gram-positive bacteria, including
S. aureus and L. monocytogenes and limits the growth of spores
of several Clostridium and Bacillus species. It has little effect on
Gram-negative bacteria, yeasts, and molds,117 but the
incorporation of chelating agents (e.g., EDTA) may enhance
its effect. It has been used with good results in meat, cheese,
and dairy products, seafood, and in the wine and beer
industries, being able to tolerate high and low temperatures
and acidity. Furthermore, it has also demonstrated ability to
prevent the progression of human squamous carcinoma cell
lines, although it also showed toxicological effects in mice.66,118
The synergistic effects of nisin with carvacrol and lysozyme, as
well as its encapsulation feasibility, have been explored with
visible success.12,100,119−121
On the other hand, reuterin appears as a broad-spectrum
antimicrobial substance, produced exclusively by the enzyme
glycerol dehydratase from L. reuteri. The high-water solubility,
heat resistance, stability over a wide range of pH values, and
lipolytic and proteolytic enzymes make it a good biopreserva-
tive for foods. It controls Gram-positive and Gram-negative
spoilage and pathogenic bacteria in milk, dairy, and meat
products and can prevent the growth of Aeromonas hydrophila,
L. monocytogenes, E. coli O157: H7, Clostridium jejuni, Y.
enterocolitica, and S. aureus.122
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Organic acids play an important role in the ability of LAB
starter cultures to inhibit undesirable microorganisms,
providing food safety. They cause a pH reduction, inhibiting
spoilage and pathogenic bacteria.123 Lactic acid is the main
compound produced in food fermentations, followed by acetic
and propionic acids. Enterococcus, Lactococcus, Lactobacillus,
Streptococcus, Pediococcus, and Leuconostoc are some of the
strains that provide lactic acid as the main product, and
yogurts, olives, sauerkrauts, and fermented sausages are mainly
maintained by this acid.124 Propionic acid is generated by
Propionibacterium in cheese.72 The hydrogen peroxide
produced by LAB is effective against spoilage and pathogenic
microorganisms such as Pseudomonas spp. and S. aureus.
Carbon dioxide is also generated during fermentation of
vegetables, such as sauerkraut, and helps to establish anaerobic
conditions, being lethal to certain aerobic food microorganisms
and having the ability to lower intracellular pH and inhibit
enzymatic reactions. It generally prevents the growth of
obligate aerobes, such as fungi, and slows the growth of
facultative microorganisms, such as Enterobacteriaceae.125
Diacetyl generated by strains from many LAB has antibacterial
activity against yeasts, fungi, and Gram-negative bacteria,
which are more susceptible to diacetyl than Gram-positive
bacteria.126 Despite being negligible to biopreservation, the
contribution of ethanol can increase the lethal effect of low pH
and lactic acid in E. coli, although at higher concentrations than
those likely to occur in lactic fermentations.127
As described, there is a wide variety of natural antimicrobial
compounds. However, some have not yet been approved as
food antimicrobials, in part due to the extensive toxicological
experiments required to ensure their safety. Consequently,
additional research is needed to discover the optimal levels of
antioxidants and antimicrobial substances that can be used
harmlessly in food systems without excessively altering sensory
or physicochemical characteristic.128
3.2. Antioxidants. In the storage process, two types of
oxidations (lipid peroxidation and rancidification) occur in
foods. Molecular oxygen oxidation is the primary degradation
process in foods; it promotes a loss of nutritional value and
produces an undesirable taste and smell.22 Auto-oxidation in
foods can occur in vitamins, but it is mostly observed in fat
(unsaturated fatty acids, cholesterol, and phospholipids).129
Beyond the impacts in the organoleptic properties, such as the
alteration of the color and texture and the induction of a rancid
taste, it also leads to the formation of toxic compounds.18,130
To prevent or delay these reactions, the food industry relies on
antioxidants, which scavenge free radicals and oxygen, stopping
peroxidation at the initiation or propagation stages, thus
prolonging the shelf life of foods and preventing their
decomposition without adding taste or odor to the food or
changing its appearance.131
The importance of separating synthetic/artificial food
additives from natural food additives is becoming more and
more necessary due to the interest in the application of the
latter. Likewise, the amounts and permissions of use of natural
and synthetic antioxidant sources in each type of food should
be added to the official tables.132
The main synthetic antioxidants used, mainly to inhibit the
oxidation of fatty acids, are BHA (E320) and BHT (E221).
BHA is used for foods and coatings, working better in animal
fats than in vegetable fats. The acceptable daily intake (ADI) is
1 mg/kg body weight (bw) and exposure of children and
adults should not exceed these doses. For its part, BHT, one of
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the cheapest antioxidants to produce, is generally used in
animal fats and dry breakfast cereals, not exceeding an ADI of
0.5 mg/kg bw.133 These antioxidants have synergistic behavior
when added to foods, deeply volatile given their chemical
structures, and methods with thermal processes such as
cooking or frying are not recommended. Their use has been
banned or limited in some countries because of their harmful
effects on human health.134 TBHQ (tert-butylhydroquinone)
(E319), also very common, has applications in meats,
margarines, cereals, and oils, but it is not efficient in the
bread and pastry industry. Gallate compounds (E310−E312)
are used alone or in combination with BHT and BHA. They
have very limited, case-specific applications but can be used in
dried milk, fats, oils, nut butters, potato products, chewing
gums, cereals, meats, nuts, and food supplements. Other EFSA-
approved chemical antioxidants include ascorbic acid and
derivatives (E300−E304), EDTA (E385), erythorbic acid
(E315), sodium erythorbate (E316), citrates (E330−E380),
lactates (E325−E327), and tartrates (E334−E354).132
Ascorbic acid (E300) is a powerful antioxidant that can be
used in practically used worldwide. It is commonly used in
combination with artificial antioxidants such as BHT and BHA
because of their excellent properties in regenerating other
antioxidants. It also has a strong association with tocopher-
ols.18 Sodium ascorbate (E301), used in several foods, was
tested in fermented dry sausages to prevent oxidation of
proteins and lipids. However, its application as a substitute for
nitrites in foods is very limited due to its pro-oxidant
behavior.135 Calcium ascorbate (E302) is used in dairy
products, cured or cooked meat products, to dip freshly cut
fruit and prevent browning, to intensify the color of cured
meat, and to act as a synergist for other antioxidants.136,137
Fatty acid esters of ascorbic acid (E304) can be used in dairy
products, chewing gums, cereals, meats, desserts, salads, sauces,
and others.138 Erythorbates (E315−E316) are mostly dis-
sipated in cured meats, frozen fruits, vegetables, oils, fats,
seafood, and fish with the function of reducing the formation
of nitrosamines during curing or cooking.139 Sodium lactate
(E325) and potassium lactate (E326) are used as antimicro-
bials in processed and unprocessed meats, sausages, meat
burgers, and fish.140−142
Citric acid (E330) is a very strong synergist, especially with
ascorbic acid and chitosan. It also prevents browning of foods
and increases their shelf life, since it also acts as a chelating
agent.143 Another strong synergist with organic acids,
specifically with citric, tartaric, malic, and lactic acids is sodium
citrate (E331), which in turn has a chelating, pH buffering,
retarding, antimicrobial, flavor-enhancing, and antioxidant
effect, being mainly used in meats and skimmed milk.144
Potassium citrate (E332) and calcium citrate (E333) are used
in jellies, marmalades, and cheeses as emulsifying agents, pH
buffers, sequestrants, and antioxidants and are mainly used to
modify intense flavors.1 Tartaric acid (E334) and its
derivatives, sodium (E335), potassium (E336), and calcium
(E336) salts, are used in chocolates, marmalades, gelatins,
canned food, and fresh pasta as well as in cheeses, fats, oils,
meats, and sausages.1,145 Phosphoric acid (E338) and its salts
synergize with citric acid to prevent fat oxidation and are used
in soft drinks, fruit jellies, cheese, and yeast powders.146
Sodium phosphate (E339) has chelating and antimicrobial
effects, which are enhanced by synergy with nisin and is
applied in pasta, meat, powdered milk, fruit, cheese, snacks,
and ready-made desserts. Potassium phosphate (E340) is used
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in meats, breads, pasta, powdered juices, eggs, pasta, and
sausages, calcium phosphate (E341) is used in the baking
industry, fruit preserves, powdered juices flour, cheese, and
porridge, and with less representation, ammonium phosphate
(E342) and magnesium phosphate (E343), which can be used
in breads, pasta, cookies, and pancakes. All are considered
GRAS molecules.1,18,36,139 Adipic acid and its salts are used in
cheeses, jellies, and canned fruit and is used synergistically with
sodium metabisulfite (E223). Succinic acid is applied to
chicken meat, dairy products, and cooked foods.1,36,139,146,147
Calcium disodium EDTA (E385) is used in foods such as
poultry meats, processed meats, vegetables, fruits, beer, and
fruit juices because it is a metal chelating compound, has
antioxidant properties, and when acting with potassium
sorbate, lysozyme, nisin, monolaurin, and monocapin increases
its antimicrobial potential. It is also often added with ascorbic
and citric acid, lecithins, BHA, BHT, and PG (propyl gallate)
for the purpose of anointing fats but also in fresh and
processed meats, fish, sauces, cereals, and seafood.1,18,36,139,148
In terms of natural antioxidant additives, rosemary extract
(E392) is an example of the use of plant extracts by the food
industry for food preservation, thus allowing the search for and
possible use of other sources of natural antioxidants. Phenolic
compounds, such as carnosic acid, rosmarinic acid, carnosol,
and rosmaridiphenol, among others, that compose the
rosemary extract and possess a great antioxidant power,26 as
it allows a wide range of applications in the European Union,
namely, in dehydrated milk, fats, processed potatoes, fine
pastry, processed and heat-treated meat, fish, and eggs,
mustard, soups, sauces, and food supplements, among others.
It has not been assigned an admissible daily intake (AID)
value, given its safety, and is considered a quantum Satis (it can
be added to food in the quantity required to achieve the
desired technological effect). It can also be used synergistically
with other antioxidants such as nisin, polyphenols, BHA, and
BHT to boost its antioxidant effect.18,149−154
3.2.1. Natural Antioxidant Preservatives. The interest in
natural antioxidants has grown exponentially, and their
importance both in vivo and in food is undeniable. Natural
and even functional additives that can be found in different
plants, fruits, algae, and mushrooms have been presented as
alternatives to synthetic additives in order to fortify and
stabilize foods. Some compounds, such as vitamins, poly-
phenols, and carotenoids can even show similar protective
effects to BHT and BHA, being described as among the most
relevant natural antioxidant compounds.18
Polyphenols are known to have a powerful antioxidant
capacity, with promising effects on human health, and due to
these properties and the ability to preserve food as well as their
good acceptance by consumers (as they are natural molecules),
their use is attractive for the food industry, especially when it
comes to replacing synthetic additives.155 The main groups of
polyphenols are phenolic acids (hydroxybenzoic and cinnamic
acids), flavonoids (anthocyanidins, flavones, flavonols, iso-
flavones, flavanols, and flavanones), lignans, and stilbenes.96,97
Among these phenolic compounds, some stand out more than
others and can be added to foods individually, after purification
of the molecules or used as plant extracts, taking advantage of
the synergistic effects between them.11 Polyphenolic plant
extracts, such as those from rosemary, previously mentioned
and identified as a food additive have been used to act as
antioxidants in foods. Despite the advantages of synergy
between compounds, preference is often given to specific
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molecules by industries. In this sense, it is believed that
carnosic acid, a derivative of the hydroxybenzoic acid
constituent of rosemary extract, has the most significant
antioxidant power, being used in oils, animal fats, sauces,
roasts, meat, and fish burgers, among others.156,157 Ferulic acid,
a hydroxycinnamic acid, is used as an antioxidant and
precursor to other preservatives and has also been employed
as part of food gels and edible films.158,159 Catechin (flavan-3-
ol) can be added directly to food, combined with other natural
substances as well as encapsulated, thus potentiating and
amplifying its effects.160 Ascorbic acid (E300), i.e., vitamin C,
can stabilize lipids and oils by helping to regenerate phenolic
oxidants and tocopherols that have undergone oxidation. EFSA
determined that its consumption is safe and did not define an
ADI.18,161
Another group of natural food additives with antioxidant
potential are carotenoids, although their use is limited because
they are very susceptible to oxidation by light. The most
common in food are lycopene, lutein, and β-carotene. They are
used in foods such as meat, fish, fruit, cereal products, pastries,
dairy products, and many others.132 The most widely used
carotenoid in food is lycopene (E160d), found mainly in
tomatoes, but it is not widely used as a food antioxidant. On
the other hand, β-carotene (E160a) is used as an oxygen
singlet in dairy products, bakery products, and eggs, among
others.147 Astaxanthin is a carotenoid pigment not approved by
the EU; this colorant has a high antioxidant capacity and is
currently being studied as a possible food preservative. The use
of carotenoids in the food industry must guarantee the stability
of these molecules during storage.162 The union of carotenoids
with ascorbic acid or vitamin E helps in synergies, and this
mixture (either synthetically or extracted from plants and
fruits) has been analyzed by the EFSA Scientific Panel,
rejecting any toxicity from their consumption.163 Another
compound with which ascorbic acid can act are tocopherols,
acting as very strong antioxidants. They are used in films and
coatings as well as in additives (E306−E309), exerting mainly
an activity against lipid peroxidation and rancidity in oils,
meats, vegetable oils, and dairy animal fats, among
others.147,164−168
There are also other carotenoids that are used as food
additives. Annatto, for example, is a mixture of several
carotenoids extracted from the Bixa orellana shrub, with
bixin being the most prominent one. Although annatto is used
as a food colorant, it can also be used as an antioxidant, and its
use against auto-oxidation of triacylglycerols in seeds has been
reported. Other reports have suggested that synergistic links
between tocopherols and norbixin allow for an increase in
antioxidant potential, the latter being recognized as a stronger
antioxidant than the former. Its use is permitted in the EU with
an ADI of 0.065 mg/kg bw and is identified with the code
E160b.169 Lutein has different biological functions, justifying
its application in the cosmetic industry for its antioxidant
capacity, especially for inhibiting lipid autoxidation in skin
cells. Its activity is even stronger than that of β-carotene. Its use
in the food industry according to EFSA is limited to being a
coloring additive in baked goods, bread-based foods, soft
drinks, and also as sauces and confectionery, not allowing its
use as a food antioxidant.18
3.3. Antibrowning Agents. During the various stages of
food production, several changes can occur in foods, such as
browning processes. In this sense, additives that can counteract
this reaction are important to maintain the stability and
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Figure 3. Schematic illustration of the development of new molecules, through new chemical approaches, with modification of already known
natural molecules to develop a better and double performance (dye plus preservative).
preservation of foods, and the most commonly used are
sulfates. Going against the current focus, natural alternatives to
these synthetic additives are compounds such as erythorbic
acid (E315), used in beverages for flavor preservation; 4-
hexylresorcinol (E586), an organic compound allowed only in
shrimp, and an amino acid, L-cysteine (E920). Their effect is
based on the reconversion of quinone intermediates to the
phenolic form and reactions with quinolone intermediates to
inhibit the formation of further compounds.1,170 Calcium
lactate is also used to inhibit the browning of foods, especially
fruits, by maintaining their structure. It is also applied
synergistically with phosphates to improve their antioxidant
capacity in meat.171,172
4. POTENTIAL COMPOUNDS WITH DUAL ACTIVITY
The food industry is in search of technological advances as well
as solutions, applications, and methodologies to obtain new
products that respond to the needs and demands of
consumers. The importance of preservative and color additives
for the preservation and marketing of food products has led to
the search for new solutions and/or improvement of existing
alternatives. In nature, there are compounds that can have the
capacity not only to stabilize or improve color but also to
prolong the shelf life of the product. The evaluation of different
natural matrixes that could have the ability to provide color
and, at the same time, could act as preservatives has been of
great interest in the food industry. Anthocyanins, carotenoids,
betalains, and their derivatives are among the compounds that
may provide these properties, owing to their pigmentation,
antioxidant capacity, and/or antimicrobial activity (Figure
3).13,173 For instance, Ab Rashid et al.174 have recently
developed an antibacterial food colorant based on anthocya-
nins from Clitoria ternatea flowers, showing a broad-spectrum
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of antibacterial activity and being able to maintain the color for
21 days at temperatures from −20 to 4 °C, making it an
alternative as a biopreservative and colorant to be used in food
products. Another study investigated the antimicrobial proper-
ties of eight food colorants extracted from plants (Acacia
catechu L., Bixa orellana L., Cassia auriculata L., Embillica
of f icinalis Gaertn, Punica granatum L., Rubia tinctorum L.,
Tagetes erecta L., and Terminalia chebula Retz.), concluding
that the red pigments had better antibacterial activity, in
contrast to the yellow pigments which showed better
antifungal activity. This study also analyzed the antioxidant
activity, where the red pigments showed again better activity
than the yellow ones; these features would allow the
incorporation of these dyes in food providing preservative
properties.175 The phenolic composition of methanolic and
ethanolic extracts of Murta (Ugni molinae Turcz) fruit was
studied for evaluation of their antioxidant and antimicrobial
activity; ethanolic extracts showed high antioxidant capacity,
while methanol extracts yielded inhibitory activity against
Escherichia coli and S. typhi bacteria similar to that of standard
antibiotics, thus opening prospects to explore these extracts as
potential biopreservatives with coloring capacity owing to their
high anthocyanin content.176 In another study, the anti-
bacterial and antifungal activity of a curcumin microcapsule
was evaluated against some foodborne pathogens and spoilage
microbes, including Escherichia coli, Yersinia enterocolitica,
Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Aspergillus
niger, Penicllium notatum, and Saccharomyces cerevisiae. The
microcapsule showed a broad-spectrum inhibitory effect
against all these microorganisms, especially against Gram-
positive bacteria; furthermore, its antifungal activity was much
better than the antibacterial activity. These results give insights
into the possibility of using microencapsulated curcumin as a
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high potential colorant and preservative in the food
industry.177
Betalains are also a good example of natural food colorants,
exhibiting not only prominent coloring attributes but also a
range of biological activities, such as antioxidant and antiradical
ability, conferring protection against oxidative damage,
antimicrobial properties, as well as antiproliferative, cytotoxic,
and neuroprotective capacities, providing health benefits
concomitantly with their coloring and preservative ca-
pacity.178−182
Another important group of compounds with dual activity
are carotenoids. Some of the most important are α-carotene, β-
carotene, and lycopene, which are already approved and used
as food colorants. They not only provide color and/or food
preservation, but their high antioxidant power makes them
excellent natural food additives, with no toxicological threat in
the amounts necessary for their use in food.12 β-carotene, a
precursor of vitamin A, has been successfully added to various
foods, especially functional beverages and nutraceuticals, and
its application in new and existing products is expected to
increase in the future. Lycopene, one of the main
phytochemicals in tomatoes, has been used to increase
stabilization, improve color, and provide health benefits
when incorporated into minced meat.132,183
However, it is important to emphasize that to obtain
functional benefits, such as antioxidant and/or antimicrobial
activity, the concentrations of compounds commonly used as
dyes are markedly different (usually higher) from those used
for dye purposes, not meeting the requirement of acceptable
daily intake (ADI) imposed by regulatory agencies so as not to
pose health hazards.5 This confirms the need for research into
new natural matrixes, which have coloring and preservative
capacity, and may jointly provide beneficial properties to the
consumer and a challenging opportunity for the scientific
community to solve, through the development of new biobased
molecules, the next generation of food additives, through new
chemical approaches, modifying the natural molecules already
known so that they develop a better and double performance
(dye plus preservative).
Noncovalent complexation is a naturally occurring process
and is the mechanism mostly responsible for stabilizing and
enhancing blue, violet, and red colors (e.g., anthocyanins) in
flowers, vegetables, and fruits as well as in food products
derived from them (wines, jams, and syrups). The concept of
copigmentation has been refined over the years, and the
atomistic perception of it has been essential to complement it
by elucidating color diversity in nature and its stabilization
process in nature.184 The increased interest in copigmentation
has been remarkable, particularly by the food industry, in order
to improve the color palette. In view of its mastery and use
through the addition of copigments to food products, accurate
(computer-aided) control of supramolecular assemblies of
noncovalent supramolecular copigments is essential.185 In this
sense, the copigmentation with antioxidant/antimicrobial
molecules can also be explored, and the use of new tools
and cheminformatic models can support the development of
unique hybrid compounds with dual function (staining and
preservation), based on the knowledge of numerous
biomolecules spawning new biobased molecules as the next
generation of food additives.186,187
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5. MOLECULAR DYNAMICS SIMULATIONS:
CHALLENGES AND OPPORTUNITIES
The delivery of technology and biofunctionality in all-natural
processed foods is an area of increasing fundamental and
technological interest.187 Physical properties and stability are
critical for delivering safe and healthy food to consumers, and
therefore it is a topic that has attracted food scientists for a
long time.188 Food is a complex system that undergoes many
physical and chemical transformations during processing and
subsequent storage. These transformations are governed by
molecular motions within the final product and reflect its
overall stability and perceived quality.189,190
Simulation-based research has been going on for a few
decades, and computer simulations of biomolecular systems
have been growing rapidly in recent years. Characterized by
detailed information about the atomic/molecular structure and
not subject to physical fallacies, molecular dynamics (MD)
simulation has been touted as the most promising tool for the
characterization of multicomponent systems and has proven to
be a useful methodology for investigating complex geometries
and molecules as well as studying structural and dynamical
properties.191 MD simulation has enabled the study of many
biological systems over the past decade, from small molecules,
such as anesthetics or small peptides, to very large protein
complexes, such as the ribosome or virus capsids.192−195
Due to the complexity of biological and nonbiological
systems, MD simulations have come under great interest for
their ability to predict and verify experimental results,
providing an opportunity to study the physical characteristics
of systems that are not easily examined in the laboratory.
Research aimed at improving MD algorithms so that they can
simulate the folding and unfolding of proteins is one example
of the study of these features.196,197 In addition to biological
applications, MD simulations have been used to study the
physical characteristics of nonbiological nanoparticles.198
Comparisons of simulation and experimental data serve to
test the accuracy of the calculated results and provide criteria
for improving the methodology.199 Another significant aspect
of the simulations is that although the potentials used in the
simulations are approximate, they are entirely under the
control of the user, so that by removing or changing specific
contributions, their role in determining a particular property
can be examined. Intensive computational processing power is
required to simulate a complex system using MD simulations.
With the available tools, it is only possible to simulate a
dynamic system in a time interval of the order of femto-
seconds. However, it is expected that, with the development of
better MD simulation software and significantly faster
computer hardware, MD simulation will become faster and
more accurate and will be performed for more extended
periods of simulation time.
Given the current demands for cleaner food, the preference
for natural additives, and the toxicity and safety issues with
synthetic additives, research into natural compounds that fulfill
dual functions is emerging. However, such compounds may
take time to become part of the additives allowed for use by
regulators, noting that in addition to research for these new
molecules, they must undergo thorough toxicity and safety
evaluation before their use becomes permissible for con-
sumption. A promising alternative would be to exploit already
existing natural additive biomolecules with accepted worldwide
use and, through new chemical approaches and modification of
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J. Agric. Food Chem. 2022, 70, 2789−2805
Journal of Agricultural and Food Chemistry
these molecules, develop unique hybrid compounds with dual
function (coloring and preservation). This is because usually
their individual use is directed only to one function, and to
exert other activities (antioxidant and/or antimicrobial) the
concentrations are usually higher than those used for dyeing
purposes, which may pose health hazards.5 In this sense, and
despite some limitations of molecular dynamics simulations,
their exploitation for research and development of these hybrid
molecules, predicting and verifying the experimental results,
allow one to study certain physical characteristics that are not
easily examined in the laboratory and very promising and can
help and accelerate research and studies on a topic that is
currently fundamental.
6. CLOSING REMARKS
The controversy and ambiguity among chemical additives have
encouraged the search for natural alternatives, which are easily
accepted by consumers. Combining the trends of health-
oriented eating and lifestyle, exercise, safe, unprocessed, and
healthy eating, there is a growing tendency to reduce the
addition of additives in food or to replace them with novel
natural additives. Nevertheless, the role they play in
maintaining and/or enhancing food quality standards still
justifies their application in the distinct production and storage
processes and, therefore, the search for innovative and effective
solutions.
Although natural compounds tend to be safer than those
produced synthetically, studies concerning toxicity, carcinoge-
nicity, and others must be conducted to ensure their safety.
Another major limitation is their actual effectiveness is that if a
large amount is required for their ability to be exerted, it may
lead to changes in the food in terms of appearance, taste, and/
or texture, so it is important to determine their effective
outcome properly, remembering that if larger quantities of
natural additives are required than synthetic ones, their use
may not be cost-effective or recommended. In addition, the
lack of appropriate legislation for natural additives (regulated
identically to synthetics) is a barrier to the approval of new
compounds/extracts and cuts across both, making it difficult to
bring new compounds to the market. Their delay is also
justified by all the trials that must be conducted to ensure
safety standards and achieve a proper ADI. Synergistic effects
and multiple functions simultaneously are common in natural
additives; however, some may be incompatible with others,
natural or artificial, as well as with the constituents of food
itself, so that their use may be impeded. Despite the described
limitations, additives of natural origin are believed to be the
future of food preservation allowing shelf life extension and
preventing food loss. By overcoming the limitations, better,
safer, and more efficient natural additives will be achieved and/
or new artificial compounds can be discovered as well as
synergistic effects between the currently approved additives. It
should be noted that all these advances and hypothetical novel
food additives are regulated by the governing bodies, and the
possible demystification, increased efficiency, and ease of
access to other types of food preservation methods may also
limit the need for additives. Concomitantly, we can count on
the advance of computer and computational methodologies,
which increasingly serve as tools to support experimental
methodologies, through in silico assays. These complement the
experimental assays that, besides making research less painful
and time-consuming, provide important data that would
otherwise be difficult to obtain. Other strategies to food
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preservation that may involve a lighter additive load are dual-
function additives, resulting from the combination of two types
of additives to perform distinct functions in foods, such as
preservative colorants. Such compounds would have undoubt-
edly to be safe, inexpensive, and not alter food. Although
difficult to accomplish, we have been much further away from
finding them.
■ AUTHOR INFORMATION
Corresponding Authors
Carla Pereira − Centro de Investigaçaõ de Montanha
(CIMO), Instituto Politécnico de Bragança, Campus de
Santa Apolónia, 5300-253 Bragança, Portugal;
Email: carlap@ipb.pt
Lillian Barros − Centro de Investigaçaõ de Montanha
(CIMO), Instituto Politécnico de Bragança, Campus de
Santa Apolónia, 5300-253 Bragança, Portugal; orcid.org/
0000-0002-9050-5189; Email: lillian@ipb.pt
Authors
Cláudia Novais − Centro de Investigaçaõ de Montanha
(CIMO), Instituto Politécnico de Bragança, Campus de
Santa Apolónia, 5300-253 Bragança, Portugal
Adriana K. Molina − Centro de Investigaçaõ de Montanha
(CIMO), Instituto Politécnico de Bragança, Campus de
Santa Apolónia, 5300-253 Bragança, Portugal
Rui M. V. Abreu − Centro de Investigaçaõ de Montanha
(CIMO), Instituto Politécnico de Bragança, Campus de
Santa Apolónia, 5300-253 Bragança, Portugal
Celestino Santo-Buelga − Grupo de Investigación en
Polifenoles (GIP-USAL), Facultad de Farmacia, Campus
Miguel de Unamuno s/n, Universidad de Salamanca, 37007
Salamanca, Spain
Isabel C. F. R. Ferreira − Centro de Investigaçaõ de
Montanha (CIMO), Instituto Politécnico de Bragança,
Campus de Santa Apolónia, 5300-253 Bragança, Portugal
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jafc.1c07533
Funding
The authors are grateful to the Foundation for Science and
Technology (FCT, Portugal) for financial support through
national funds FCT/MCTES to CIMO (Grant UIDB/00690/
2020); national funding by F.C.T. and P.I., through the
Institutional Scientific Employment Program-Contract for C.P.
and L.B. contracts and C.N. (Grant 2021.05369.BD) and
A.K.M. (Grant 2020.06231.BD) Ph.D. grants. The authors
acknowledge the FEDER-Interreg Españ a-Portugal Pro-
gramme for financial support through the Project TRANS-
CoLAB 0612_TRANS_CO_LAB_2_P; to ERDF through the
Regional Operational Program North 2020, within the scope of
Project Mobilizador Norte-01-0247-FEDER-024479: Valor-
Natural. The GIP-USAL is financially supported by the
Spanish “Ministerio de Ciencia and Innovación” (Grant
PID2019-106167RB-I00) and “Junta de Castilla y León”
(Grants SA093P20 and CLU-2018-04).
Notes
The authors declare no competing financial interest.
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